Mitochondrial dysfunction has long been implicated in the pathogenesis of Parkinson’s disease (PD). Evidence first emerged following the observation that accidental exposure of drug abusers to 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), an inhibitor of complex I of the mitochondrial electron transport chain, resulted in an acute and irreversible parkinsonian syndrome almost indistinguishable from PD. After the discovery that MPTP causes SNpc DA cell death in humans, non-human primates, and in various other mammalian species, this neurotoxin has been used extensively as an experimental animal model of PD. A biochemical link between MPTP toxicity and sporadic PD was subsequently established when several groups reported reduced complex I activity in the SNpc, platelets and skeletal muscle of patients with PD. In addition, cell lines engineered to contain mitochondria derived from platelets of PD patients (cybrids) also exhibit reduced complex I activity. In addition, many disease-causing proteins associated with familial forms of PD have been demonstrated to interact either directly or indirectly with mitochondria,

Mitochondria are highly dynamic organelles with complex structural features which play several important cellular functions, such as the production of energy by oxidative phosphorylation, the regulation of calcium homeostasis, or the control of programmed cell death (PCD). Given its essential role in neuronal viability, alterations in mitochondrial biology can lead to neuron dysfunction and cell death. While defects in mitochondrial respiration have long been implicated in the etiology and pathogenesis of PD, new evidence indicate that the role of mitochondria in PD extends well beyond defective respiration and also involves perturbations in mitochondrial dynamics, leading to alterations in mitochondrial morphology, intracellular trafficking, or quality control. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of dopaminergic neurodegeneration in PD.

Mitochondrial dysfunction in PD. Alterations in several aspects of mitochondria biology have been linked to the pathogenesis of PD, such as: (a) reduced complex I activity, (b) increased production of mitochondria-derived ROS, (c) ROS-mediated mtDNA damage, (d) bioenergetic failure, (e) Bax-mediated cytochrome c release and activation of mitochondria-dependent apoptotic pathways, (f) defective mitophagy, or (g) increased mitochondrial Ca2+-buffering burden. Many of the mutated nuclear genes linked to familial forms of PD, including PINK1, Parkin, α-synuclein, DJ-1 or LRRK2, have been shown to affect many of these mitochondrial features (see main text for details). CL, cardiolipin; Cyt. c, cytochrome c; HTRA2, high temperature requirement A2; IMM, inner mitochondrial membrane; IMS, intermembrane space; LRRK2, leucine-rich-repeat kinase 2; OMM, outer mitochondrial membrane PINK1, phosphatase and tensin homolog-induced kinase 1; ROS, reactive oxygen species; TRAP1, tumor necrosis factor receptor-associated protein 1; α-syn, alpha-synuclein. From Perier & Vila, Cold Spring Harbor Perspectives in Medicine (2012)

Additional reading:

Mitochondrial biology and Parkinson’s disease.
Perier C. and Vila M.
Cold Spring Harbor Perspectives in Medicine 2(2):a009332 (2012)

Mitochondria and programmed cell death in Parkinson’s disease: apoptosis and beyond.
Perier C., Bové J. and Vila M.
Antioxidants & redox signaling 16(9):883-95 (2012)

Apoptosis inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins.
Perier C., Bové J., Dehay, B., Jackson-Lewis, V., Rabinovitch P.S., Przedborski, S. and Vila M.
Annals of Neurology 68:184-192 (2010)

Two molecular pathways initiate mitochondria-dependent dopaminergic neurodegeneration in experimental Parkinson’s disease.
Perier C., Bové J., Wu D.C., Jackson-Lewis V., Dehay B., Choi D.G., Rathke-Hartlieb S., Bouillet P., Strasser A., Schulz J.B., Przedborski S. and Vila M.
Proceedings of the National Academy of Sciences USA 104(19):8161-6 (2007)

Complex I deficiency primes Bax-dependent neuronal apoptosis through mitochondrial oxidative damage.
Perier C., Tieu K., Guegan C., Caspersen C., Jackson-Lewis V., Carelli V., Martinuzzi A., Hirano M., Przedborski S. and Vila M.
Proceedings of the National Academy of Sciences USA, 102(52):19126-19131 (2005)